Buprenorphine
Buprenorphine is a semi-synthetic, mixed μ agonist-κ-antagonist opioid receptor modulator that is used to treat opioid addiction in higher dosages, to control moderate acute pain in non-opioid-tolerant individuals in lower dosages and to control moderate chronic pain in even smaller doses. Its structure is:

Buprenorphine is currently indicated for the treatment of pain as intravenous, sublingual and transdermal dosage forms. Buprenorphine is also indicated for the treatment of opiate addiction. Although buprenorphine has a long half-life and can be administered once daily, the oral bioavailability of buprenorphine is very low due to extensive presystemic extraction. Consequently sublingual administration of buprenorphine is required to achieve clinically effective systemic plasma concentrations. Even with sublingual administration, buprenorphine is only about 30% available to systemic circulation.
Diarrhea-Predominant Irritable Bowel Syndrome
Diarrhea-predominant irritable bowel syndrome (IBS-D) is a highly prevalent gastrointestinal disorder that is often accompanied, in addition to diarrhea, by both visceral and somatic hyperalgesia (enhanced pain from colorectal and somatic stimuli), discomfort, bloating, and gas.
According to the International Foundation for Functional Gastrointestinal Disorders, IBS-D is estimated to affect between 25-45 million Americans. It is the most common diagnosis made by gastroenterologists, and is one of the disorders most frequently treated by primary care physicians.
Irritable bowel syndrome has a very heavy impact on the quality of life and has high social costs. The disease has a fluctuating trend, but tends to be chronic or subchronic. Although there is no evidence that the presence of IBS involves deterioration in patient life expectancy, it significantly reduces health-related quality of life and work productivity. In the more severe cases patients may experience several episodes of abdominal pain and diarrhea per day resulting in severe impairment of relationships and in the workplace.
IBS-D Treatments
Bile acid binders, amitryptyline, probiotics, mast cell stabilizers and 5-ASA have been used off-label in the treatment of IBS-D, albeit without compelling evidence of chronic efficacy. The anti-diarrheal loperamide, a synthetic opioid, has been used similarly, but its uninhibited full opioid agonist activity often results in severe constipation.
Among drugs in development for IBS-D is LX 1033, an inhibitor of serotonin synthesis in the gastro-intestinal tract, currently being developed by Lexicon Pharmaceuticals. Its mechanism of action, however, does not support pain alleviation. DNK-333 (Novartis), a neurokinin antagonist, was withdrawn from study for IBS-D following Phase II studies for want of efficacy. Ibodutant (Menarini), another neurokinin antagonist in Phase II trials, showed no efficacy over placebo in the overall population, and is being pursued in further testing only in women. Rifaximin (Salix Pharmaceuticals) has been studied for IBS-D, showing moderate activity, but there is significant concern for the development of antibiotic resistance and continued efficacy.
Latronex (alosetron, Prometheus Laboratories, Inc.) is the only drug approved for IBS-D in the United States, albeit only for women. It has no demonstrated analgesic properties. Importantly, it has a black box warning for serious adverse effects including, specifically, ischemic colitis.
To date, no drug has been approved in the United States for chronic, unrestricted treatment of IBS-D.
Eluxadoline (Forest Laboratories, Inc.) is a μ opioid receptor agonist and δ opioid receptor antagonist that has met primary endpoints of improvement of stool consistency and reduction of abdominal pain in Phase III testing. Its effect on pain reduction is modest at best and without a demonstrable effect on reducing colonic hypersensitivity that results in hyperalgesia. Moreover, several cases of pancreatitis, a potentially life threatening disease, were reported in Phase II trials. Cases of pancreatitis were reported even after patients with a known history of biliary disease were excluded from clinical study enrollment. In general, μ agonists have a constricting effect on the Sphincter of Oddi, a muscular valve that regulates the flow of bile and pancreatic juice from the bile duct into the duodenum. Buprenorphine, because of its partial μ agonist effect and κ antagonist effect, does not result in increased tone or constriction of the Sphincter of Oddi. We expect that the buprenorphine dimer, with the same receptor pharmacology as buprenorphine, will also have no constricting effect on the Sphincter of Oddi.
There has accordingly been a long-standing need for a chronic treatment of IBS-D that decreases intestinal motility, thereby decreasing the incidence of diarrhea, is an analgesic, is not associated with pancreatitis, and more than merely treating symptoms, potentially addresses underlying hypersensitivity and resulting hyperalgesia associated with IBS-D.